Findings Confirm Benefits of Albumin in Treating Cirrhosis Patients Undergoing Large-Volume Paracentesis

PRESS RELEASE

March 28, 2012, 2:29 p.m. EDT

KING OF PRUSSIA, Pa., March 28, 2012 /PRNewswire via COMTEX/ -- Administration of albumin reduces morbidity and mortality in cirrhotic patients undergoing large-volume paracentesis due to severe ascites, according to a new meta-analysis published online today in Hepatology, the official journal of the American Association for the Study of Liver Diseases. Compared with alternative treatments, albumin, a natural plasma-derived protein that expands blood plasma volume, significantly reduced the circulatory dysfunction that often occurs after large-volume paracentesis and also significantly reduced the occurrence of hyponatremia (low blood sodium levels). In addition, risk of death was 36 percent lower in patients receiving albumin than in those receiving other treatments.

"Albumin is the gold standard for preventing circulatory dysfunction following paracentesis greater than five liters. However, other volume expanders as well as vasoconstrictors have been considered as potential alternatives," said Mauro Bernardi, M.D., Professor of Internal Medicine at Bologna University, Bologna, Italy and lead author of the meta-analysis. "Our findings, which combine all the available evidence from randomized clinical trials, confirm that albumin is the best choice for prevention of circulatory dysfunction, and for the first time show decreased incidence of hyponatremia and improved survival with albumin use."

Within 10 years of receiving a diagnosis, the majority of patients with liver cirrhosis develop ascites, or fluid accumulation in the abdominal cavity. Symptoms include abdominal swelling, major discomfort and impaired breathing often necessitating hospitalization. Patients with ascites have a poor prognosis, with a 50 percent mortality rate over two years. To relieve the pressure caused by the excessive abdominal fluid, a procedure called paracentesis uses a needle to drain the fluid from the abdominal cavity. However, the abrupt removal of large amounts of fluid can worsen existing circulatory dysfunction, leading to a reduction in effective volemia that adversely affect the kidney and other organs.

The meta-analysis, which included results from 17 randomized clinical trials with 1,225 total patients, found that albumin reduced the risk of post-paracentesis circulatory dysfunction by 61 percent compared with alternative treatments. The analysis also found that the risk of hyponatremia, a condition associated with worsening brain function and death, was decreased 42 percent with albumin administration compared to other treatments, further supporting the well-accepted clinical practice of infusing albumin as the first choice in adjunctive treatment for patients requiring large-volume paracentesis.

About CSL Behring

CSL Behring is a global leader in the plasma protein biotherapeutics industry. Passionate about improving the quality of patients' lives, CSL Behring manufactures and markets a range of safe and effective plasma-derived and recombinant products and related services. The company's therapies are used in the treatment of immune deficiency disorders, hereditary angioedema, haemophilia, von Willebrand disease, other bleeding disorders and inherited emphysema. Other products are used for the prevention of hemolytic diseases in the newborn, in cardiac surgery, organ transplantation and in the treatment of burns. The company also operates one of the world's largest plasma collection networks, CSL Plasma. CSL Behring is a subsidiary of CSL Limited, a biopharmaceutical company with headquarters in Melbourne, Australia. For more information, visit www.cslbehring.com .

Contact:Sheila A. Burke, Director, Communications & Public RelationsWorldwide Commercial OperationsCSL Behring 610-878-4209 (o)484-919-2618 (c)Sheila.Burke@cslbehring.com 

SOURCE CSL Behring

Source

HIV and hepatitis C survival in used syringes

Uploaded by HarmReductionWorks on May 8, 2009

An description of the experiments done at Yale university to find out how long HIV and hepatitis C can survive in used syringes.

Protease inhibitors: Silver bullets for chronic hepatitis C infection?

doi: 10.3949/ccjm.79a.11082

Cleveland Clinic Journal of Medicine March 2012 vol. 79 3 213-222

1. NAIM ALKHOURI, MD

1. Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH

1. NIZAR N. ZEIN, MD^*⇓

+ Author Affiliations

1. Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH

1. ADDRESS: Nizar N. Zein, MD, Department of Gastroenterology and Hepatology, A31, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail zeinn@ccf.org.

Abstract

Recent trials evaluated the safety and efficacy of two protease inhibitors, boceprevir (Victrelis) and telaprevir (Incivek), added to standard care with pegylated interferon and ribavirin, in patients with chronic hepatitis C virus (HCV) infection. These drugs open the door for triple therapy and other new therapies involving combinations of other direct-acting antiviral agents to become the new standard of care for this population.

Key points

Standard care with the combination of pegylated interferon and ribavirin produces a sustained virologic response in about 40% of patients infected with HCV genotype 1, the most prevalent genotype in North America.

New phase 3 trials showed that the addition of an oral protease inhibitor (boceprevir or telaprevir) increased the sustained virologic response rates to 70% in patients infected with HCV genotype 1.

Boceprevir and telaprevir must be used in combination with pegylated interferon and ribavirin; they should not be used as monotherapy because of concern about the development of drug-resistant mutations.

The main side effects of boceprevir were anemia and dysgeusia. Adverse events associated with telaprevir included rash, pruritus, anemia, and diarrhea.

The treatment of hepatitis c virus (HCV) infection is on the brink of major changes with the recent approval of the first direct-acting antiviral agents, the protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek).

Both drugs were approved by the US Food and Drug Administration (FDA) Advisory Panel for Chronic Hepatitis C in May 2011 and are believed to significantly improve treatment outcomes for patients with HCV genotype 1 infection.

This review summarizes the results of recent phase 3 clinical trials that evaluated the safety and efficacy of these new agents (TABLE 1).^1–5

A MAJOR PUBLIC HEALTH PROBLEM

HCV infection is a major public health problem. Nearly 4 million people in the United States are infected.^6,7 Most patients with acute HCV infection become chronically infected, and up to 25% eventually develop cirrhosis and its complications, making HCV infection the leading indication for liver transplantation.^8–10

Chronic HCV infection has a large global impact, with 180 million people affected across all economic and social groups.¹¹ The highest prevalence of HCV has been reported in Egypt (14%), in part due to the use of inadequately sterilized needles in mass programs to treat endemic schistosomiasis. In developed countries, hepatocellular carcinoma associated with HCV has the fastest growing cancer-related death rate.¹²

TABLE 1 Phase III clinical trials of boceprevir and telaprevir

 

CURRENTLY, FEWER THAN 50% OF PATIENTS ARE CURED

The goal of HCV treatment is to eradicate the virus. However, most infected patients (especially in the United States and Europe) are infected with HCV genotype 1, which is the most difficult genotype to treat.

Successful treatment of HCV is defined as achieving a sustained virologic response—ie, the absence of detectable HCV RNA in the serum 24 weeks after completion of therapy. Once a sustained virologic response is achieved, lifetime “cure” of HCV infection is expected in more than 99% of patients.¹³

The current standard therapy for HCV, pegylated interferon plus ribavirin for 48 weeks, is effective in only 40% to 50% of patients with genotype 1 infection.¹⁴ Therefore, assessing predictors of response before starting treatment can help select patients who are most likely to benefit from therapy.

Viral factors associated with a sustained virologic response include HCV genotypes other than genotype 1 and a low baseline viral load.

Beneficial patient-related factors include younger age, nonblack ethnicity, low body weight (≤ 75 kg), low body mass index, absence of insulin resistance, and absence of advanced fibrosis or cirrhosis.

More recently, a single-nucleotide polymorphism near the interleukin 28B (IL28B) gene, coding for interferon lambda 3, was found to be associated with a twofold difference in the rates of sustained virologic response: patients with the favorable genotype CC were two times more likely to achieve a sustained virologic response than patients with the CT or TT genotypes.^15–17

PROTEASE INHIBITORS: MECHANISM OF ACTION

HCV is a single-stranded RNA virus, and its genome encodes a single polyprotein of about 3,000 amino acids. This polyprotein is cleaved by proteases during and after translation into four structural and six nonstructural proteins. The NS3/4A protease plays an important role in viral replication by cleaving the HCV polyprotein and releasing most of the nonstructural proteins (FIGURE 1).^18,19

^{(Click on picture to enlarge)}

FIGURE 1.

TABLE 2 Adverse events reported in clinical trials of boceprevir and telaprevir

NS3/4A protease inhibitors rely on the principle of end-product inhibition, in which the cleavage product of the protease (a peptide) acts to inhibit the enzyme activity; this is why they are called peptidomimetics. The active site of the NS3/4A protease is a shallow groove composed of three highly conserved amino acid residues, which may explain why protease inhibitors display high antiviral efficacy but pose a low barrier to the development of resistance.²⁰

Protease inhibitors are prone to resistance

The development of viral resistance to protease inhibitors has been a major drawback to their use in patients with chronic HCV infection.²¹

HCV is a highly variable virus with many genetically distinct but closely related quasispecies circulating in the blood at any given time. Drug-resistant, mutated variants preexist within the patient’s quasispecies, but only in small quantities because of their lesser replication fitness compared with the wild-type virus.²² When direct-acting antiviral therapy is started, the quantity of the wild-type virus decreases and the mutated virus gains replication fitness. Using protease inhibitors as monotherapy selects resistant viral populations rapidly within a few days or weeks.

HCV subtypes 1a and 1b may have different resistance profiles. With genotype 1a, some resistance-associated amino acid substitutions require only one nucleotide change, but with genotype 1b, two nucleotide changes are needed, making resistance less frequent in patients with HCV genotype 1b.²³

BOCEPREVIR

Boceprevir is a specific inhibitor of the HCV viral protease NS3/4A.

In phase 3 clinical trials, boceprevir 800 mg three times a day was used with pegylated interferon alfa-2b (PegIntron) 1.5 μg/kg/week and ribavirin (Rebetol) 600 to 1,400 mg daily according to body weight.

Before patients started taking boceprevir, they went through a 4-week lead-in phase, during which they received pegylated interferon and ribavirin. This schedule appeared to reduce the incidence of viral breakthrough in phase 2 trials, and it produced higher rates of sustained virologic response and lower relapse rates compared with triple therapy without a lead-in phase.

Rapid virologic response was defined as undetectable HCV RNA at week 4 of boceprevir therapy (week 8 of the whole regimen).

Boceprevir in previously untreated patients with HCV genotype 1: The SPRINT-2 trial

The Serine Protease Inhibitor Therapy 2 (SPRINT-2) trial¹ included more than 1,000 previously untreated adults with HCV genotype 1 infection (938 nonblack patients and 159 black patients; two other nonblack patients did not receive any study drug and were not included in the analysis). In this double-blind trial, patients were randomized into three groups:

• The control group received the standard of care with pegylated interferon and ribavirin for 48 weeks

• The response-guided therapy group received boceprevir plus pegylated interferon and ribavirin for 24 weeks after the 4-week lead-in phase; if HCV RNA was undetectable from week 8 to week 24, treatment was considered complete, but if HCV RNA was detectable at any point from week 8 to week 24, pegylated interferon and ribavirin were continued for a total of 48 weeks.

• The fixed-duration therapy group received boceprevir, pegylated interferon, and ribavirin for 44 weeks after the lead-in period.

In the overall cohort, the rates of sustained virologic response were 63% in the response-guided therapy group and 66% in the fixed-duration therapy group compared with 38% in the control group (P < .001 for both) (TABLE 2). In the subgroup of patients who were black, the rates were 42%, 53%, and 23%, respectively. Overall, 44% of patients in the response-guided therapy group were able to stop all treatment at 28 weeks.

The rate of relapse was 8% and 9% in the boceprevir groups vs 23% in the control group. Patients in the boceprevir groups who had a decrease in HCV RNA of less than 1 log₁₀ during the lead-in phase were found to have a significantly higher rate of boceprevirresistant variants than those who achieved a decrease of HCV RNA of 1 log₁₀ or more.

Boceprevir in previously treated patients with HCV genotype 1: The RESPOND-2 trial

The Retreatment With HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2) (RESPOND-2) trial² was designed to assess the efficacy of combined boceprevir, pegylated interferon, and ribavirin for repeat treatment of patients with HCV genotype 1. These patients had previously undergone standard treatment and had a reduction of 2 log₁₀ or more in HCV RNA after 12 weeks of therapy but with detectable HCV RNA during the therapy period or had had a relapse (defined as undetectable HCV RNA at the end of a previous course of therapy with HCV RNA positivity thereafter). Importantly, null-responders (those who had a reduction of less than 2 log₁₀ in HCV RNA after 12 weeks of therapy) were excluded from this trial.

After a lead-in period of interferon-ribavirin treatment for 4 weeks, 403 patients were assigned to one of three treatment groups:

• Pegylated interferon and ribavirin for 44 weeks (the control group)

• Boceprevir, pegylated interferon, and ribavirin in a response-guided regimen

• Boceprevir, pegylated interferon, and ribavirin for 44 weeks (the fixed-duration group).

Sustained virologic response was achieved in only 21% of patients in the control group. Adding boceprevir increased the rate to 59% in the response-guided therapy group and to 67% in the fixed-duration group. Previous relapsers had better rates than partial responders (69%–75% vs 40%–52%).

Importantly, patients who had a poor response to pegylated interferon and ribavirin during the lead-in phase (defined as having less than a 1-log decrease in the virus before starting boceprevir) had significantly lower rates of sustained virologic response and higher rates of resistance-associated virus variants.

Side effects of boceprevir

Overall, boceprevir is well tolerated. The most common side effects of triple therapy are those usually seen with pegylated interferon and ribavirin, such as flulike symptoms and fatigue (TABLE 2). However, anemia was more frequent in the boceprevir groups in both SPRINT-2 and RESPOND-2 (45%–50% compared with 20%–29% in the control groups). Erythropoietin was allowed in these studies and was used in about 40% of patients.

The other common side effect associated with boceprevir was dysgeusia (alteration of taste). Dysgeusia was reported by approximately 40% of patients; however, most dysgeusia events were mild to moderate in intensity and did not lead to treatment cessation.

In the SPRINT-2 trial,¹ the study drugs had to be discontinued in 12% to 16% of patients in the boceprevir groups because of adverse events, which was similar to the rate (16%) in the control group. Erythropoietin was allowed in this trial, and it was used in 43% of patients in the boceprevir groups compared with 24% in the control group, with discontinuation owing to anemia occurring in 2% and 1% of cases, respectively.

TELAPREVIR

Telaprevir, the other protease NS3/4A inhibitor, has also shown efficacy over current standard therapy in phase 3 clinical trials. It was used in a dose of 750 mg three times a day with pegylated interferon alfa-2a (Pegasys) 180 μg per week and ribavirin (Copegus) 1,000 to 1,200 mg daily according to body weight. A lead-in phase with pegylated interferon and ribavirin was not applied with telaprevir, as it was in the boceprevir trials. Extended rapid virologic response was defined as an undetectable HCV RNA at weeks 4 and 12 of therapy.

Telaprevir in previously untreated patients with HCV genotype 1

The ADVANCE study³ was a double-blind randomized trial assessing the efficacy and safety of telaprevir in combination with pegylated interferon and ribavirin in more than 1,000 previously untreated patients. The three treatment groups received:

• Telaprevir, pegylated interferon, and ribavirin for 8 weeks, followed by pegylated interferon and ribavirin alone for 16 weeks in patients who achieved an extended rapid virologic response (total duration of 24 weeks) or 40 weeks in patients who did not (total duration of 48 weeks)

• Telaprevir, pegylated interferon, and ribavirin for 12 weeks, followed by pegylated interferon-ribavirin alone for 12 (total of 24 weeks) or 36 weeks (total of 48 weeks) according to extended rapid virologic response

• Standard care with pegylated interferon and ribavirin for 48 weeks.

The rate of sustained virologic response was 69% in the group that received telaprevir for 8 weeks and 75% in the group that received it for 12 weeks compared with 44% in the control group (P < .0001 for both) (TABLE 2). Patients infected with HCV genotype 1b had a higher sustained virologic response rate (79%) than those infected with HCV genotype 1a (71%).

Sustained virologic response rates were lower in black patients and patients with bridging fibrosis or cirrhosis, but were still significantly higher in the telaprevir groups than in the control group. The results of this subset analysis were limited by small numbers of patients in each category.

In total, 57% of those who received telaprevir for 8 weeks and 58% of those who received it for 12 weeks achieved an extended rapid virologic response and were able to cut the duration of their therapy in half (from 48 weeks to 24 weeks).

The relapse rates were 9% in the telaprevir groups and 28% in the control group.

The rate of virologic failure was lower in patients who received triple therapy than in those who received interferon-ribavirin alone (8% in the group that got telaprevir for 12 weeks and 13% in the group that got it for 8 weeks, vs 32% in the control group). The failure rate was also lower in patients with HCV genotype 1b infection than in those with genotype 1a.

The ILLUMINATE study⁴ (Illustrating the Effects of Combination Therapy With Telaprevir) investigated whether longer duration of treatment than that given in the ADVANCE trial increased the rate of sustained virologic response. Previously untreated patients received telaprevir, interferon, and ribavirin for 12 weeks, and those who achieved an extended rapid virologic response were randomized at week 20 to continue interferonribavirin treatment for 24 or 48 weeks of total treatment.

The sustained virologic response rates in patients who achieved an extended rapid virologic response were 92% in the group that received pegylated interferon and ribavirin for 12 weeks, and 88% in those who received it for 48 weeks. Thus, the results of this study support the use of response-guided therapy for telaprevir-based regimens.

Telaprevir in previously treated patients with HCV genotype 1: The REALIZE trial

In this phase 3 placebo-controlled trial,⁵ 622 patients with prior relapse, partial response, or null response were randomly allocated into one of three groups:

• Telaprevir for 12 weeks plus pegylated interferon and ribavirin for 48 weeks

• Lead-in for 4 weeks followed by 12 weeks of triple therapy and another 32 weeks of pegylated interferon and ribavirin

• Pegylated interferon and ribavirin for 48 weeks (the control group).

The overall sustained virologic response rates were 66% and 64%, respectively, in the telaprevir groups vs 17% in the control group (P < .0001). The sustained virologic response rates in the telaprevir groups were 83% to 88% in prior relapsers, 54% to 59% in partial responders, and 29% to 33% in null-responders. Of note, patients did not benefit from the lead-in phase.

This was the only trial to investigate the response to triple therapy in null-responders, a group in which treatment has been considered hopeless. A response rate of approximately 31% was encouraging, especially if we compare it with the 5% response rate achieved with the current standard of care with pegylated interferon and ribavirin.

Telaprevir side effects

As with boceprevir-based triple therapy, the most common adverse events were related to pegylated interferon (TABLE 2).

Nearly 50% of patients who receive telaprevir develop a skin rash that is primarily eczematous, can be managed with topical steroids, and usually resolves when telaprevir is discontinued. Severe rashes occurred in 3% to 6% of patients in the ADVANCE trial,³ and three suspected cases of Stevens-Johnson syndrome have been reported to the FDA.

Other side effects that were more frequent with telaprevir included pruritus, nausea, diarrhea, and anemia. On average, the hemoglobin level decreased by an additional 1 g/dL in the telaprevir treatment groups compared with the groups that received only pegylated interferon-ribavirin. Erythropoietin use was not allowed in the phase 3 telaprevir studies, and anemia was managed by ribavirin dose reduction.

In the ADVANCE trial,³ study drugs were discontinued owing to adverse events in 7% to 8% of the patients in the telaprevir groups compared with 4% in the control group. In the ILLUMINATE trial,⁴ 17% of patients had to permanently discontinue all study drugs due to adverse events.

FDA-APPROVED TREATMENT REGIMENS FOR BOCEPREVIR AND TELAPREVIR

For treatment algorithms, see the eFIGURES that accompany this article online.

Boceprevir in previously untreated patients

• Week 0—Start pegylated interferon and ribavirin

• Week 4—Add boceprevir

• Week 8—Measure HCV RNA

• Week 12—Measure HCV RNA; stop treatment if it is more than 100 IU/mL

• Week 24—Measure HCV RNA; stop treatment if it is detectable

• Week 28—Stop all treatment if HCV RNA was undetectable at weeks 8 and 24

• Week 36—Measure HCV RNA; stop boceprevir

• Week 48—Stop all treatment (eFIGURE 1).

Boceprevir in previously treated patients

• Week 0—Start pegylated interferon and ribavirin

• Week 4—Add boceprevir

• Week 8—Measure HCV RNA

• Week 12—Measure HCV RNA; stop treatment if it is more than 100 IU/mL

• Week 24—Measure HCV RNA; stop treatment if it is detectable

• Week 36—if HCV RNA was not detectable at week 8, stop all treatment now; if HCV RNA was detectable at week 8, stop boceprevir now but continue pegylated interferon and ribavirin

• Week 48—Stop all treatment (eFIGURE 2).

Telaprevir in previously untreated patients and prior relapsers

• Week 0—start telaprevir, pegylated interferon, and ribavirin

• Week 4—measure HCV RNA; stop all treatment if it is more than 1,000 IU/mL

• Week 12—Stop telaprevir; measure HCV RNA; stop all treatment if HCV RNA is more than 1,000 IU/mL

• Week 24—Stop pegylated interferon and ribavirin if HCV RNA was undetectable at week 12; measure HCV RNA and stop treatment if it is detectable; otherwise, continue pegylated interferon and ribavirin

• Week 48—Stop all treatment (eFIGURE 3).

Telaprevir in patients who previously achieved a partial or null response

• Week 0—Start telaprevir, pegylated interferon, and ribavirin

• Week 4—Measure HCV RNA; stop treatment if it is more than 1,000 IU/mL

• Week 12—Measure HCV RNA; stop all treatment if it is more than 1,000 IU/mL; if less than 1,000 IU/mL then stop telaprevir but continue pegylated interferon and ribavirin

• Week 24—Measure HCV RNA; stop treatment if HCV RNA is detectable

• Week 48—Stop all treatment (eFIGURE 4).

Drug interactions with boceprevir and telaprevir

Both boceprevir and telaprevir inhibit cytochrome P450 3A (CYP3A) and thus are contraindicated in combination with drugs highly dependent on CYP3A for clearance and with drugs for which elevated plasma concentrations are associated with serious adverse events, such as atorvastatin (Lipitor), simvastatin (Zocor), sildenafil (Viagra), midazolam (Versed), and St. John’s wort. Giving potent inducers of CYP3A with boceprevir or telaprevir may lead to lower exposure and loss of efficacy of both protease inhibitors.

EMERGING THERAPIES FOR HCV

Thanks to a better understanding of the biology of HCV infection, the effort to develop new therapeutic agents started to focus on targeting specific steps of the viral life cycle, including attachment, entry into cells, replication, and release.²⁴

Currently, more than 50 clinical trials are evaluating new direct-acting antivirals to treat HCV infection.²⁵ Monoclonal and polyclonal antibodies that target the molecular process involved in HCV attachment and entry are being developed.²⁶ The nonstructural protein NS5B (RNA polymerase) is intimately involved in viral replication and represents a promising target.²⁷ Several nucleosides and nonnucleoside protease inhibitors have already entered clinical trials.

The low fidelity of the HCV replication machinery leads to a very high mutation rate, thus enabling the virus to quickly develop mutations that resist agents targeting viral enzymes.²⁸ Therefore, a novel approach is to target host cofactors that are essential for HCV replication. An intriguing study by Lanford et al²⁹ demonstrated that antagonizing microRNA-122 (the most abundant microRNA in the liver and an essential cofactor for viral RNA replication) by the oligonucleotide SPC3649 caused marked and prolonged reduction of HCV viremia in chronically infected chimpanzees.²⁹

Although we are still in the early stages of drug development, the future holds great promise for newer drugs to improve the sustained virologic response, shorten the duration of treatment, improve tolerability with interferon-sparing regimens, and decrease viral resistance.

FUTURE PERSPECTIVES

With the introduction of the first direct-acting antiviral medications for HCV (boceprevir and telaprevir), 2011 will be marked as the year that changed hepatitis C treatment for the better. Triple therapy with pegylated interferon, ribavirin, and either boceprevir or telaprevir has the potential for increasing the rate of sustained virologic response to around 70% in previously untreated patients and 65% in previously treated patients who are infected with HCV genotype 1. The IL28B polymorphisms appear to play a role in the rate of sustained virologic response achieved with triple therapy, with preliminary data showing a better response rate in patients who have the CC genotype.¹⁷

These drugs will add up to $50,000 to the cost of treating hepatitis C virus infection, depending on the drug used and the length of treatment. However, they may be well worth it if they prevent liver failure and the need for transplantation.

Many questions remain, such as how to use these new regimens to treat special patient populations—for example, those with a recurrence of HCV infection after liver transplantation, those co-infected with HCV and human immunodeficiency virus, and those infected with HCV genotypes other than genotype 1.

Other direct-acting antiviral agents that specifically target the replication cycle of HCV are currently in clinical development. In fact, the future has already started with the release of the Interferon-Free Regimen for the Management of HCV (INFORM-1) study results.³⁰ This was the first trial to evaluate an interferon-free regimen for patients with chronic HCV infection using two direct-acting antiviral drugs (the protease inhibitor danoprevir and the polymerase inhibitor RG7128), with promising results.

Footnotes

• ↵* Dr. Zein has disclosed consulting, teaching, speaking, and receiving research funding from Merck (makers of boceprevir) and Vertex (makers of telaprevir).

• Copyright© 2012 The Cleveland Clinic Foundation

References

Source

IL28B Genetic Variants and Gender Are Associated With Spontaneous Clearance of Hepatitis C Virus Infection

From Journal of Viral Hepatitis

H.-Y. Rao; D.-G. Sun; D. Jiang; R.-F. Yang; F. Guo; J.-H. Wang; F. Liu; H.-Y. Zhang; H.-H. Zhang; S.-C. Du; Q. Jin; H. Qin; A.-S.-F. Lok; L. Wei

Posted: 03/28/2012; J Viral Hepat. 2012;19(3):173-181. © 2012 Blackwell Publishing

Abstract and Introduction

Abstract

Single nucleotide polymorphisms (SNPs) near the IL28B gene have been shown to be associated with response to treatment for chronic hepatitis C and also with spontaneous clearance of hepatitis C virus (HCV) infection. We analysed the association between IL28B genetic variants and spontaneous clearance of HCV infection in 376 HCV-infected Chinese paid plasma donors. Genotyping of eight SNPs near the IL28B region was performed by the iPLEX system (MassARRAY® SNP Genotyping; Sequenom) in all donors, and sequencing was performed on all 80 donors who cleared HCV and on 160 of 296 donors who did not clear HCV to validate the genotypes. Eighty (21.3%) donors spontaneously cleared HCV. Four SNPs were significantly associated with spontaneous HCV clearance: rs8099917 TT (vs GT), rs8105790 TT (vs CT), rs12980275 AA (vs AG) and rs10853728 CC (vs CG or GG) with OR (95% CI) 15.27 (2.07–112.50), 14.88 (2.02–109.72), 7.92 (1.88–33.32) and 2.32 (1.22–4.42) respectively. No association between the other four IL28B SNPs including rs12979860 and spontaneous HCV clearance was found. Women had a higher rate of spontaneous HCV clearance than men [56/213 (26.3%) vs 24/163 (14.6%), P = 0.007], and this was true even after stratification for IL28B genotypes with OR of 1.9–2.2 among those with favourable genotypes. Our results confirmed that IL28B polymorphism is associated with spontaneous clearance of HCV in Chinese subjects, but the SNPs that predict HCV clearance in Chinese subjects were different from those reported in Caucasians. Women were more likely to clear HCV infection regardless of IL28B genotypes.

Introduction

Hepatitis C virus (HCV) infection is rated by the World Health Organization as a global health problem, based on its prevalence, the high rate (50–85%) of chronicity, the rate of severe complications such as cirrhosis and hepatocellular carcinoma, as well as the high costs of antiviral therapy and liver transplantation.^[1–3]

There is a significant difference in response to treatment with pegylated interferon plus ribavirin in patients of different race or ethnicity, with sustained virological response rates of 28%, 34%, 52% and 76% in African American, Hispanic, Caucasian American and Asian patients respectively with genotype 1 HCV infection.^[4–7] Likewise, racial differences in the rate of spontaneous viral clearance have been reported.^[8,9] These racial differences suggest a genetic influence on HCV outcome.

Ge et al.^[10] identified a key role for variation in a region close to the interleukin-28B (IL28B) gene on chromosome 19, which codes for interferon-lambda-3, in predicting response to pegylated interferon plus ribavirin therapy in patients with genotype 1 chronic HCV infection. This finding has been confirmed in other independent cohorts.^[11–13] In addition, the IL28B single nucleotide polymorphism (SNP) most strongly associated with treatment response, rs12979860, has also been shown to be significantly associated with spontaneous hepatitis C clearance.^[14–16] Tanaka et al.^[17] found other SNPs in close proximity to IL28B that were associated with treatment response in Japanese patients, with rs8099917 and rs12980275 having the strongest association. Rauch et al.^[12] also reported that rs8099917 was significantly associated with treatment response as well as with spontaneous clearance of HCV infection in Swiss and German patients. An association between rs8099917 and spontaneous HCV clearance was also shown in a study of Spanish patients.^[18]

Data on the association between IL28B genetic variants and treatment response or spontaneous viral clearance in Chinese patients with HCV infection are limited. In a study of 2371 persons from different continents, Thomas et al.^[14] found that the frequency of the C allele at rs12979860 was roughly 95% among Chinese, 70% among Caucasians and 25–40% among Africans. Ge et al.^[10] noted that the linkage between rs12979860 and rs8099917 is high among Caucasians but low among African Americans. These data suggest that the IL28B variants that have the strongest association with spontaneous HCV clearance and response to HCV treatment in different racial/ethnic groups may be different.

Between 1972 and 1990, several outbreaks of non-A, non-B hepatitis linked to plasma donation occurred at plasmapheresis centres in Hebei Province Guan County, China. These donors have been followed for 12–19 years after initial documentation of HCV infection and roughly 20% have cleared HCV infection spontaneously. This cohort provided a unique opportunity to evaluate the role of host genetics in the outcome of HCV infection in a population with fairly homogenous ethnic background. Here, we present data on the association between IL28B genetic variation and spontaneous HCV clearance in these HCV-infected plasma donors.

Patients and Methods

Patient Population

Commercial plasma donation was introduced in China in the 1970s. Prior to each donation, the donors were required to have normal alanine aminotransferase (ALT) and no evidence of hepatitis B virus (HBV) infection based on negative test result for hepatitis B surface antigen (HBsAg). Nevertheless, incidences of non-A and non-B hepatitis continued to occur, and multiple outbreaks among six villages and one town occurred in Hebei Province Guan County between 1972 and 1990. The cause of these outbreaks was believed to be related to the return of red cells to donors through contaminated transfusion lines. Post-transfusion non-A, non-B hepatitis outbreaks also occurred among the plasma recipients; however, this study was focused on the donors.

After hepatitis C testing became available, donors from five villages and one town were tested for hepatitis C antibody (anti-HCV) in 1991, and donors from the sixth village were tested for anti-HCV in 1998. Of the 864 registered paid donors, 792 (91.7%) came back for anti-HCV testing and 450 (56.8%) of these 792 tested positive. Donors who tested positive for anti-HCV were invited to return for follow-up assessment every 5–6 years between 1991 and 2008 and once a year thereafter. At each visit, the donors were evaluated and blood was tested for anti-HCV and ALT. HCV RNA was tested during follow-up visits in 2002, 2009 and 2010. All donors who previously tested positive for anti-HCV were invited to participate in a study of IL28B genetic variation during their follow-up visit in 2010. Blood was drawn for biochemical tests, HCV RNA, HCV genotype and IL28B SNPs during the 2010 visit. HCV clearance was defined as undetectable HCV RNA on at least two follow-up evaluations including the visit in 2010 in subjects who were anti-HCV positive during initial screening in 1991 or 1998. All donors in our study were of Han ancestry.

The Ethical Committee of Human Experimentation in Peking University People's Hospital approved the study, and the study was performed in accordance with the Helsinki Declaration of 1975. The plasma donors were enrolled after providing written informed consent for the follow-up study, and additional consent for genetic testing was provided during the 2010 visit.

Biochemical Tests

Fasting blood samples collected at each follow-up visit were tested for ALT, aspartate aminotransferase (AST), γ-glutamyltransferase (γ-GT), alkaline phosphatase, total bilirubin (TBil), direct bilirubin, total protein and albumin by an automated biochemical analyser 7600 (Hitachi, Tokyo, Japan).

Virology Tests

Tests for anti-HCV were carried out using enzyme immunoassay (Chiron, Emeryville, CA, USA) between 1991 and 2005 and chemiluminescent microparticle immunoassay (Architect; Abbott, Chicago, IL, USA) after 2005. HCV RNA was quantified with real-time fluorescence quantitative assay (PG Biotech Company, Shenzhen, China) that has a lower limit of detection of 500 IU/mL between 2002 and 2008 and with Cobas Ampliprep/Cobas Taqman HCV assay (Roche Molecular Diagnostics, Branchburg, NJ, USA) that has a lower limit of detection of 15 IU/mL after 2008. HCV genotype was determined with restriction fragment length polymorphism.^[19] HBsAg (Abbott) and anti-HIV were detected by enzyme immunoassay (BioMérieux, Boxtel, the Netherlands).

IL28B SNPs Genotyping

The genomic region associated with response to hepatitis C treatment identified by Ge et al.^[10] and Tanaka et al.^[17] contains several highly linked SNPs around the IL28B gene. In our cohort, we selected the following SNPs for genotyping: rs12979860, rs10853728, rs11881222, rs12980275, rs4803219, rs4803223, rs8099917 and rs8105790. DNA from the subjects was extracted from peripheral blood using standard methods. Genotyping was performed by the iPLEX system (MassARRAY® SNP Genotyping; Sequenom, San Diego, CA, USA) for all 376 donors. DNA from the donors was blind coded and tested using a 384 format SpectroCHIP™ microarray (Sequenom). A matrix-assisted laser desorption/ionization time-of-flight mass spectrometer was used for data acquisitions from the SpectroCHIP™. Results were analysed using Sequenoms MassARRAY RT™ software (Sequenom). To validate the results of the iPLEX system, we sequenced the region surrounding the IL28B gene that covered the eight SNPs for all donors who cleared HCV and a random selection of approximately 50% of the donors who did not clear HCV. Samples were amplified, and the amplicons were subjected to direct sequencing using the Big Dyes Termination version 1.1 kit (ABI) and the ABI Prism 3730 genetic analyser (Applied Biosystems, Foster City, CA, USA). Sequence results were analysed using Polyphred software (Applied Biosystems). Results of the iPLEX system and direct sequencing were compared.

Statistical Analysis

Genotype frequencies were obtained by direct counting, and statistical analysis was performed by the chi-square test. Qualitative data were also analysed by the chi-square test and odds ratio (OR) with 95% confidence intervals (95% CI). Median values of quantitative variables were compared using a nonparametric test (Mann–Whitney two-tailed test). P-values <0.05 were considered statistically significant. The statistical software package used was SPSS 13.0 for Windows (SPSS Inc., Chicago, IL, USA).

Results

Rate of Spontaneous HCV Clearance

Of the 450 donors who tested positive for anti-HCV in 1991 or 1998, 36 had died (18 because of liver diseases), and 33 were lost to follow-up by May 2010 (Fig. 1). Five donors with HBV co-infection were excluded. The remaining 376 HCV-infected plasma donors were tested for IL28B SNPs, 163 were men and 213 women, with a mean age of 53.2 ± 8.0 years and a mean BMI of 24.5 ± 3.2 (kg/m²) at the time of the study. None of the donors had received hepatitis C treatment because all of them were farmers and their medical insurance did not cover hepatitis C treatment. All the donors were serum anti-HIV negative. Eighty (21.3%) donors had spontaneous clearance of HCV infection (95% CI: 17.1–25.4). All 80 remained anti-HCV positive in 2010; of these, 70 had sample/cutoff (S/CO) ratio ≥5 and 10 had S/CO ratio <5 on the anti-HCV test in 2010.

(Click on picture to enlarge)

Figure 1. Flow diagram showing the disposition of 864 registered plasma donors.

Spontaneous viral clearance was more likely to occur in women than in men, 26.3% (56/213) vs 14.7% (24/163) (P = 0.007). As the donors were not regularly followed up before 1991 or 1998 and most had no symptoms of acute hepatitis during the outbreaks, the onset of infection and the severity of the acute infection could not be ascertained. There was no correlation between age at the time of study and spontaneous HCV clearance. All the donors had ALT tested at least once during the outbreaks, and 153 (40.7%) had elevated ALT on more than one occasion during the outbreaks. The rate of spontaneous HCV clearance was similar in donors with and without elevated ALT during the outbreaks [39/153 (25.5%) vs 41/223 (18.4%) P = 0.10].

During the 2010 visit, donors who had persistent HCV infection had significantly higher mean ALT, AST and γ-GT and lower platelet count than those who cleared HCV. Of the 296 donors who were still HCV RNA positive, 83.8%, 12.8% and 3.4% had HCV genotype 1b, 2a and 1b/2a infection, respectively.

Frequency of IL28B SNPs

Analysis of the IL28B genotype results of 240 donors (80 with spontaneous HCV clearance and 160 with persistent HCV infection) who were tested by both the iPLEX system and by sequencing showed a concordance rate of 97.8–100% for the eight SNPs studied; therefore, the results of the iPLEX system will be presented in this study.

Of the 376 donors, 180 (48.5%, 95% CI: 43.4–53.6) were homozygous for CC, 189 (50.9%, 95% CI: 45.9–56.0) were heterozygous (CT) and only 2 (0.5%, 95% CI: −0.2–1.3) were homozygous for TT at rs12979860, reflecting a C allele frequency of 74.0% (95% CI: 70.8–77.2). Frequency of the other IL28B SNPs is shown inTable 1. No significant deviations in standard genotype quality control according to the Hardy–Weinberg Equilibrium for six SNPs were noted (rs12979860, rs10853728, rs12980275, rs4803223, rs8099917 and rs8105790), while there were significant deviations for two SNPs (rs11881222 and rs4803219).

Association Between IL28B SNPs and Spontaneous Clearance of HCV Infection

Spontaneous HCV clearance was associated with four of the eight IL28B SNPs tested. The IL28B genetic variants rs8099917 [TT vs GT, OR 15.3 (95% CI: 2.1–112.5), P = 0.002], rs8105790 [TT vs CT, OR 14.9 (95% CI: 2.0–109.8), P = 0.0024], rs12980275 [AA vs AG, OR 7.9 (95% CI: 1.9–33.3), P = 0.0043] and rs10853728 [CC vs CG or GG, OR 2.3 (95% CI: 1.2–4.4), P = 0.0206] were associated with a significantly higher rate of spontaneous clearance of HCV (Table 2). Thus, for rs8099917, the SNP with the strongest association with spontaneous HCV clearance, 24.1% of TT homozygous subjects (77/319; 95% CI: 19.4–28.8) and only 2.0% (1/49, 95% CI: 1.9–6.0) of GT heterozygous subjects had spontaneous clearance of HCV.

The other four IL28B SNPs including rs12979860 were not associated with the spontaneous clearance of HCV infection. For rs12979860, spontaneous HCV clearance was observed in 24% (43/180, 95% CI: 17.7–30.1), 19.1% (36/189, 95% CI: 13.5–24.7) and 50% (1/2, 95% CI: 19.3–119.3) subjects with CC, CT and TT genotypes respectively (P = 0.33).

As women had a higher rate of spontaneous HCV clearance than men, the prevalence of favourable genotypes between men and women was compared, and the results showed no significant difference between men and women for all eight SNPs studied (Table 1). Women were significantly more likely to have spontaneous HCV clearance than men even after stratification for IL28B genotype with odds ratio of 1.9–2.2 among those with favourable genotypes (Table 3). As an example, among those with rs8099917 TT genotype, 29.5% women but only 16.9% men had spontaneous HCV clearance, OR 2.1 (95% CI: 1.2–3.6), P = 0.0093.

Haplotype Analysis

Pair-wise linkage disequilibrium between the SNPs is shown in Fig. 2. Four SNPs (rs12980275, rs8105790, rs12979860 and rs8099917) were in strong linkage disequilibrium. The haplotype ATCT with favourable alleles in these four SNPs was not associated with spontaneous HCV clearance. However, donors with the haplotype ATTC, favourable alleles in the four SNPs that were independently shown to be associated with spontaneous HCV clearance (rs12980275, rs8105790, rs8099917 and rs10853728) were significantly more likely to have spontaneous HCV clearance than those who did not have this haplotype, 24.8% (64/258) vs 13.5% (14/104), OR 2.1 (95% CI: 1.1–4.0), P = 0.018.

Figure 2. Pair-wise linkage disequilibrium pattern of the IL28 region. The degree of linkage disequilibrium between any two SNPs is described by r² values (among 0.97–1.00). Rs12980275, rs8105790, rs12979860 and rs8099917 are within a genomic block that encompasses the IL28B gene.

Multivariate Analysis of Factors Associated With Spontaneous HCV Clearance

Multivariate analysis including the following variables – gender, the four IL28B SNPs that were significant on univariate analysis and the haplotype ATTC comprising rs12980275, rs8105790, rs8099917 and rs10853728 – showed that IL28B SNP rs8099917 (OR = 14.88, 95% CI: 2.02–109.7, P = 0.008) was the most significant factor associated with spontaneous HCV clearance. Addition of the other three IL28B SNPs or the haplotype ATTC to the SNP rs8099917 did not improve the association with spontaneous HCV clearance.

Gender had an independent effect on spontaneous HCV clearance, the odds ratio for women to clear HCV infection in the multivariate model for all donors was 1.95 (95% CI: 1.14–3.32), for donors with rs8099917 TT was 2.05 (95% CI: 1.18–3.53) and for donors with the haplotype ATTC was 1.97 (95% CI: 1.09–3.55) when compared with men.

Association Between IL28B Genotype and HCV RNA Level and HCV Genotype

Analysis of the HCV RNA levels of the 276 subjects who had detectable HCV RNA at the 2010 visit showed that there was no difference in HCV RNA levels between the subjects with favourable and those with unfavourable genotypes at the four IL28B SNPs shown to be associated with spontaneous HCV clearance. There was also no difference in the distribution of HCV genotypes between the subjects with favourable and those with unfavourable IL28B genotypes.

Discussion

In this study of 376 HCV-infected Chinese paid plasma donors, we found that IL28B gene variants were significantly associated with the spontaneous clearance of HCV infection. The SNP that had the strongest association with spontaneous clearance of HCV infection was rs8099917, and persons with the TT genotype were 15 times more likely to clear HCV than those with the GT genotype. However, the SNP rs12979860 that has been shown to be most strongly associated with response to pegylated interferon and ribavirin and to spontaneous HCV clearance in Caucasians and African Americans was not associated with spontaneous HCV clearance in our study.^[10–14]

Thomas et al.^[14] studied 1008 subjects in six independent cohorts and found that rs12979860 CC genotype was predictive of spontaneous HCV clearance among individuals of both European and African ancestry. An association between rs12979860 CC genotype and spontaneous HCV clearance was also shown by Tillmann et al.^[16] who studied 190 German women and by Montes-Cano et al.^[18] in a study of 353 Spanish subjects. In all three studies, only one SNP (rs12979860) was tested. An association between rs8099917 TT genotype and response to pegylated interferon and ribavirin treatment had been reported in the studies of Caucasian patients and Japanese patients with chronic HCV infection.^[11,12,17] An association between rs8099917 TT genotype and spontaneous clearance of HCV infection was also demonstrated in a study of 132 predominantly Caucasian patients in Australia and a study of 1362 Swiss and German patients.^[12,15] Only two SNPs (rs8099917 and rs12980275) were tested in the study in Australia. The study in Switzerland tested more than 500 000 SNPs. Analysis of data from 1213 individuals with available data at both rs12979860 and rs8099917 found that rs12979860 genotype was highly associated with chronic HCV infection and was in strong linkage disequilibrium with rs8099917.^[12]

In this study, we tested eight SNPs and found an association between spontaneous HCV clearance and four SNPs including rs8099917, rs8105790, rs12980275 and rs10853728 but not rs12979860. Ge et al.^[10] had noted that the linkage between rs8099917 and rs12979860 is high among Caucasians, but low among African Americans. We found that rs8099917 was strongly linked to rs12979860 (r² = 1.00), rs12980275 (r² = 0.97) and rs8105790 (r² = 1.00) in our study. In our study, all donors with rs12979860 CC had rs8099917 TT genotype, but donors with rs12979860 CT could be rs8099917 TT or TG.

The rs12979860 C allele frequency in the Chinese Han population (83 subjects from Beijing, China) was reported to be 93.4% in HapMap and 94–98% in Thomas' study of 47 Chinese in Taiwan and 59 Chinese in San Francisco, but it was only 74% in our study. The rs8099917 T allele frequency in the Chinese Han population was reported to be 93.5% in HapMap and 93.3% in our study. The subjects in our study all came from one county, Hebei, in the northern part of China. So, the SNP allele frequencies in our study might be only representative of the northern local region. While most Chinese in the major cities of China are of Han ancestry, other ancestries predominate in some parts of China. Studies involving larger numbers of Chinese in different regions of China are necessary to determine the precise frequency of the favourable alleles at rs12979860 and rs8099917 among Chinese of various ancestries.

In this study, the SNP rs8099917 had the strongest association with spontaneous HCV clearance. Although three other SNPs (rs10853728, rs 12980275 and rs8105790) in the IL28B region were independently associated with spontaneous HCV clearance, inclusion of these three SNPs or the haplotype ATTC with favourable alleles at these three SNPs plus rs8099917 did not improve the prediction of spontaneous HCV clearance in the multivariate model compared with rs8099917 alone. Several studies showed that women were more likely to undergo spontaneous HCV clearance than men. One study of 67 persons with acute HCV infection, 66% of whom were injection drug users, found that HCV clearance occurred in 34% of women compared with 3% of men (P < 0.001).^[20] Another study followed 135 injection drug users with incident HCV infection and found that the age-adjusted hazard ratio of spontaneous HCV clearance for women was 2.91 (95% CI: 1.68–5.03).^[21] A systematic review of 31 longitudinal studies that included 314 subjects showed that the relative risk of spontaneous HCV clearance for men was 0.43 (95% CI: 0.36–0.53) (P = 0.00001).^[22]

Two recent studies examined gender, IL28B genetic variants and spontaneous HCV clearance. In Grebely et al.'s^[15] study of 132 Australians, rs8099917 TT genotype (adjusted hazard ratio 3.78, 95% CI: 1.04–13.76) was the only factor predicting spontaneous HCV clearance on multivariate analysis, but female gender and jaundice during the acute illness were not. In Montes-Cano et al.'s^[18] study of 352 Spanish subjects, rs12979860 CC genotype was associated with a higher rate of spontaneous HCV clearance in both men (72.4%vs 27.6%) and women (72.5%vs 27.5%) compared with those with CT or TT genotype. In this study, we found that women had a higher rate of spontaneous HCV clearance than men, 26.3%vs 14.6%, and this difference persisted even after stratification for IL28B genotypes. Among those with rs8099917 TT genotype, women were twice as likely to have spontaneous HCV clearance as men. Female gender remained an independent predictor of spontaneous HCV clearance in the multivariate model, with OR of 1.95.

Some studies found that the presence of jaundice or symptoms during acute HCV infection was associated with a higher rate of spontaneous HCV clearance.^[15,16,22] Tillmann et al.^[16] found that jaundice during acute infection was associated with an increased chance of spontaneous HCV clearance (42.9%vs 13.7%) in persons with non-CC genotype at rs12979860, but not in those with CC genotype (56.3%vs 60.6%). In this study, spontaneous HCV clearance rate was similar in donors with and without documented ALT elevation during the outbreaks, but the donors were not regularly monitored, and it is possible that ALT was not tested at the time of acute infection. We were also not able to determine whether any of the donors had symptomatic illness or were jaundiced during the acute infection.

In summary, in this study of a large homogenous cohort of HCV-infected plasma donors, we found that 21.3% had spontaneous HCV clearance. We confirmed that IL28B genotype is associated with spontaneous HCV clearance with rs8099917 TT genotype showing the strongest association, while rs12979860 CC genotype had no association. Women had a higher rate of spontaneous HCV clearance regardless of IL28B genotype. Our results suggest that while IL28B genotype is associated with spontaneous HCV clearance in patients of diverse racial/ethnic background, the SNP with the strongest association may vary. Further studies are needed to confirm this observation and to clarify whether other factors such as gender and severity of the acute illness are independent predictors of spontaneous HCV clearance after correction for IL28B genotype. These results will help in determining which patients with acute HCV infection should start on antiviral therapy and which ones to be monitored.

References

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2. Sweeting MJ, De Angelis D, Brant LJ, Harris HE, Mann AG, Ramsay ME. The burden of hepatitis C in England. J Viral Hepat 2007; 14: 570–576.
3. Global Burden of Hepatitis C Working Group. Global burden of disease for hepatitis C. J Clin Pharmacol 2004; 44: 20–29.
4. Conjeevaram HS, Fried MW, Jeffers LJ et al. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology 2006; 131: 470–477.
5. Jeffers LJ, Cassidy W, Howell CD, Hu S, Reddy KR. Peginterferon alfa-2a (40 kD) and ribavirin for black American patients with chronic HCV genotype 1. Hepatology 2004; 39: 1702–1708.
6. Rodriguez-Torres M, Jeffers LJ, Sheikh MY et al. Peginterferon alfa-2a and ribavirin in Latino and non-Latino whites with hepatitis C. N Engl J Med 2009; 360: 257–267.
7. Liu CH, Liu CJ, Lin CL et al. Pegylated interferon-alpha-2a plus ribavirin for treatment-naive Asian patients with hepatitis C virus genotype 1 infection: a multicentre, randomized controlled trial. Clin Infect Dis 2008; 47: 1260–1269.
8. Thomas DL, Astemborski J, Rai RM et al. The natural history of hepatitis C virus infection: host, viral, and environmental factors. JAMA 2000; 284: 450–456.
9. Aborsangaya KB, Dembinski I, Khatkar S, Alphonse MP, Nickerson P, Rempel JD. Impact of aboriginal ethnicity on HCV core-induced IL-10 synthesis: interaction with IL-10 gene polymorphisms. Hepatology 2007; 45: 623–630.
10. Ge D, Fellay J, Thompson AJ et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461: 399–401.
11. Suppiah V, Moldovan M, Ahlenstiel G et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet 2009; 41: 1100–1104.
12. Rauch A, Kutalik Z, Descombes P et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genomewide association study. Gastroenterology 2010; 138: 1338–1345.
13. McCarthy JJ, Li JH, Thompson A et al. Replicated association between an IL28B gene variant and a sustained response to pegylated interferon and ribavirin. Gastroenterology 2010; 138: 2307–2314.
14. Thomas DL, Thio CL, Martin MP et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009; 461: 798–801.
15. Grebely J, Petoumenos K, Hellard M et al. Potential role for interleukin- 28B genotype in treatment decision-making in recent hepatitis C virus infection. Hepatology 2010; 52: 1216–1224.
16. Tillmann HL, Thompson AJ, Patel K et al. A polymorphism near IL28B is associated with spontaneous clearance of acute hepatitis C virus and jaundice. Gastroenterology 2010; 139: 1586–1592.
17. Tanaka Y, Nishida N, Sugiyama M et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet 2009; 41: 1105–1109.
18. Montes-Cano MA, García-Lozano JR, Abad-Molina C et al. Interleukin-28B genetic variants and hepatitis virus infection by different viral genotypes. Hepatology 2010; 52: 33–37.
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Source

The Medicine Cabinet-Ask the Harvard Experts: What can I do for a fatty liver?

By Howard LeWine, M.D., Tribune Media Services Premium Health News Service

March 28, 2012

Q: A recent blood test revealed abnormally high liver enzymes. My doctor says I have fatty liver disease. I've started eating artichokes (after reading these were good for your liver), as well as cutting back on my food intake. I'm also eating lots of vegetables and beans, and plan to exercise more and drink less alcohol. Do you think these measures might help?

A: Yes, you're off to a great start.

Having a fatty liver means that an excess of triglycerides (one type of fat) have accumulated inside liver cells. This condition is also known as steatosis. When the fat causes the liver to be inflamed, liver enzymes are released into the blood. Doctors call this steatohepatitis.

The primary causes of fatty liver are weight gain, overuse of alcohol, diabetes, and insulin resistance. Insulin resistance means that the body has become less responsive to rising blood sugar levels. To compensate, the pancreas has to make more insulin and send it into the blood stream. Higher blood levels of insulin slow down the normal turnover of triglycerides in liver cells, so they build up.

Most often, people with fatty livers don't have any symptoms. Like you, many people are diagnosed when a blood test shows elevated liver enzymes. Or a doctor detects an enlarged liver during a physical exam. Sometimes, a large fatty liver is seen on an ultrasound or CT scan of the abdomen when the test is ordered for some other reason.

Untreated steatohepatitis can progress to cirrhosis of the liver -- a serious condition where the liver becomes unable to do its job of cleaning toxins out of the bloodstream.

Eating healthier and decreasing alcohol use should help. But in my mind, it's not enough. I recommend complete abstinence from alcohol and cutting calories to lose weight.

Exercise is a must. You can start slow, but you do want to progress to a minimum of 30 minutes of dedicated aerobic exercise daily. An hour of moderate intensity exercise most days of the week would be best.

I'm not sure if eating artichokes will help. But they surely won't hurt as long as you don't dip them in butter or mayonnaise.

(Howard LeWine, M.D., is a practicing internist at Brigham and Women's Hospital, Boston, Mass., and Chief Medical Editor of Internet Publishing at Harvard Health Publications, Harvard Medical School.)

(For additional consumer health information, please visit www.health.harvard.edu.)

Source

India is facing high rate of liver disease death due to lack of liver donors

28 March 2012

India is facing a crisis for donor livers and a statistics available said that only 500 patients out of 20,000 those who are eligible for liver transplants are getting their donor livers.

Subhash Guptha, the senior consultant for liver transplant at Apollo hospital said at the 22nd annual conference of the Indian Society of Organ Transplantation (ISOT) that a new statistics is needed for India to detail the fresh demand-supply ratio for liver transplants.

Gupta remarked that the need of liver transplantations in the western countries are mainly because of the alcohol abuse and obesity where as India is seen with the factors that are preventive.

Sandeep Guleria, the organizing secretary of ISOT said that the transplantation of human organs amendment bill recently passed by the Government of India will surely help India to have more donor livers and it will encourage cadaveric organ donation and also will improve the situation to get liver from brain-dead persons by counseling their family members. He also said that this amendment will also reduce the incidence of illegal trade of human organs.

The conference remarked that India is still low by having only a fewer specialists and liver care centre and added that the cost of liver transplant is high by Rs. 15 lakh.

Source

2 to 5 % diagnosed with hepatitis C’ in Kuwait

Updated on: 28/03/2012

Kuwait New kidney cultivation center to be established

KUWAIT CITY, March 27: Around two to five percent of the population in Kuwait had been diagnosed with Hepatitis C, reports Al-Seyassah daily quoting Dr Ahmad Al-Fadhli, an expert in digestive system and liver diseases.

Affirming the percentage is below the international average, Al-Fadhli revealed the World Health Organization (WHO) has recorded 170 million Hepatitis C cases globally.

He said around four million people in the US suffer from the disease and about 30,000 acquire it every year and 8,000 deaths have been registered.

He added one to five percent of those infected with the virus may have liver cancer 20 years after diagnosis.

Al-Fadhli also confirmed the discovery of a new Hepatitis C medicine (Victrelis) and it will be available locally within the next few weeks.

He asserted Kuwait is one of the first GCC countries to avail of the medicine, which had been approved by the concerned authorities in developed Western nations.

Meanwhile, Minister of Health Dr Ali Al-Obaidi says the Council of Ministers agreed during the meeting 13/2012 to establish a new health center for kidney cultivation in Sabah Specialist Medical Center, reports Al-Seyassah daily.

Dr Al-Obaidi added that the Popular Committee raised funds worth KD 3 million for this purpose, saying this contribution from the committee reflects the existence of good human values in Kuwait.

Meanwhile, Health Promotion Department will inaugurate a new clinic for early detection of diseases in Rumaithiya Medical Center in the presence of Director of Hawally Health Zone and Director of Health Promotion Department.

Source

ICVH 2012: Study Supports Need for HCV Testing Guidance

From Medscape Medical News

Megan Brooks

March 28, 2012 (New York, New York) — In the United States, testing for hepatitis C virus (HCV) infection is happening most often in the people least likely to be infected with the virus, according to a study presented here at the International Conference on Viral Hepatitis 2012.

"Hepatitis C is primarily a disease of older men, but they aren't the ones actually getting tested. The majority of testing is happening in young women. I'm not sure anyone has ever shown this before," study presenter Camilla S. Graham, MD, MPH, from Vertex Pharmaceuticals in Cambridge, Massachusetts, told Medscape Medical News.

There is a need for targeted age-based guidelines for HCV testing, Dr. Graham said. Roy M. Gulick, MD, from Weill Cornell Medical College in New York City, agrees. "Focused testing for hepatitis C makes sense," he told attendees during his keynote address. HCV testing recommendations are currently being developed by the US Centers for Disease Control and Prevention.

Wrong Sex, Wrong Age Group

An estimated 4.1 million Americans (1.6% of the population) are infected with HCV; the majority of these individuals were born between 1945 and 1965. Dr. Graham said the goal of her study was "to see who exactly is being tested in the United States right now."

She and her colleagues analyzed HCV testing and diagnosis rates in the commercially insured and Medicare populations from 2004 to 2008 using the Thomson Medstat MarketScan commercial database and the Medicare 5% database.

They identified individuals tested for HCV using outpatient claims with Current Procedural Terminology codes for anti-HCV antibody or HCV RNA diagnostic tests. They used International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes to identify individuals diagnosed with HCV infection.

They found that in 2008, the HCV testing rate was 1.1% in the commercially insured population and 1.7% in the Medicare population, which might explain the high proportion of undiagnosed individuals, the researchers say.

"Overall, practically nobody was getting tested, although it went up from 2004 to 2008. There are other data to support this level of testing in the United States," Dr. Graham noted.

Only 32.8% of the tests were performed in baby boomers born between 1945 and 1965, who are at the highest risk for HCV infection; 48.2% of HCV tests were performed in individuals born between 1970 and 1989.

"Eighty-one percent of people with hepatitis C in this country were born between 1945 and 1965, but we found that only a third of the tests were actually happening in that age group," Dr. Graham told Medscape Medical News. "Conversely, younger people had almost half of the tests."

In the younger (commercially insured) population, women were more likely than men to be tested; 62.0% of HCV tests were performed in women, most of whom were in their reproductive years. In the Medicare population, testing was more evenly distributed between men and women.

As expected, rates of diagnosis were consistently higher in the older (Medicare) population — the baby boomers — than in the younger population. They were also higher in men.

Women and men born between 1970 and 1989 had a 0.45% and 1.18% rate, respectively, of HCV diagnosis after testing. "Almost none of these young women had hepatitis C," Dr. Graham noted. "But when you look at the baby boomer men, between 5.7% and 7.4% of them had hepatitis C."

Help on the Way

Dr. Graham noted that "an estimated 800,000 people in the United States have cirrhosis. Within the next 10 years, it will be about 1 million people, and 75% of those people are men. Men are disproportionately likely to have hepatitis C and disproportionately more likely to develop severe fibrosis with hepatitis C."

"Clearly, we need a lot of education on who to test for hepatitis C," Dr. Graham said, adding that the forthcoming age-based screening guidelines for HCV testing should help. "The focus will be on people born between 1945 and 1965 who are at highest risk for the infection. We should have them sometime this year," Dr. Graham said.

Dr. Graham reports being an employee and stock owner of Vertex Pharmaceuticals, which commissioned the study. Dr. Gulick reports financial relationships with Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Merck & Co., and ViiV Healthcare.

International Conference on Viral Hepatitis (ICVH) 2012: Abstract 79332. Presented March 27, 2012.

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Celexa (citalopram hydrobromide) - Drug Safety Communication: Revised Recommendations, Potential Risk of Abnormal Heart Rhythms

Posted 03/28/2012]

AUDIENCE: Psychiatry, Cardiology

ISSUE: FDA is clarifying dosing and warning recommendations for the antidepressant Celexa (citalopram hydrobromide; also available in generic form). In August 2011, FDA issued a Drug Safety Communication (DSC) stating that citalopram should no longer be used at doses greater than 40 mg per day because it could cause potentially dangerous abnormalities in the electrical activity of the heart. Citalopram use at any dose is discouraged in patients with certain conditions because of the risk of QT prolongation, but because it may be important for some of those patients to use citalopram, the drug label has been changed to describe the particular caution that needs to be taken when citalopram is used in such patients. The revised drug label also describes lower doses that should be used in patients over 60 years of age.

Read the FDA Drug Safety Communication for additional information.

BACKGROUND: Celexa (citalopram hydrobromide; also available in generic form) is in a class of antidepressants called selective serotonin reuptake inhibitors (SSRIs).

RECOMMENDATIONS:

• Citalopram is not recommended for use at doses greater than 40 mg per day because such doses cause too large an effect on the QT interval and confer no additional benefit.
• Citalopram is not recommended for use in patients with congenital long QT syndrome, bradycardia, hypokalemia, or hypomagnesemia, recent acute myocardial infarction, or uncompensated heart failure.
• Citalopram use is also not recommended in patients who are taking other drugs that prolong the QT interval.
• The maximum recommended dose of citalopram is 20 mg per day for patients with hepatic impairment, patients who are older than 60 years of age, patients who are CYP 2C19 poor metabolizers, or patients who are taking concomitant cimetidine (Tagamet) or another CYP2C19 inhibitor, because these factors lead to increased blood levels of citalopram, increasing the risk of QT interval prolongation and Torsade de Pointes.

See the FDA Drug Safety Communication for additional recommendations for healthcare professionals and patients.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

• Complete and submit the report Online: www.fda.gov/MedWatch/report.htm¹
• Download form² or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

[03/28/2012 - Drug Safety Communication³ - FDA]

Previous MedWatch Alert:

[08/24/2011⁴]

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Steven Weinman, M.D., Ph.D. and his colleagues battle a virus on behalf of 3.2 million Americans

Steven Weinman M.D., Ph.D

March 26, 2012

By Alissa Poh

As diseases go, hepatitis C should be highly treatable, even curable. Like other viruses, it speedily replicates inside the cells of its host and dodges drugs by frequently mutating. One crucial difference, however, is that hepatitis C doesn't stay dormant in the body.

"If you can turn hepatitis C's replication off completely for three or more months, you're rid of it," says Steven Weinman, M.D., Ph.D., a professor of Internal Medicine and director of translational research at the University of Kansas Medical Center's Liver Center.

An estimated 3.2 million Americans, including roughly one in 33 baby boomers, are infected with hepatitis C. According to the Centers for Disease Control and Prevention, more Americans die from this infection each year than from HIV-related causes. So the fact that hepatitis C is potentially curable should be good news.

But there's a paradox. "The current drug regimen for hepatitis C is a difficult ordeal that many patients struggle to tolerate," Weinman says.

Hepatitis C patients typically undergo a year-long course of interferon and ribavirin; both boost the immune system but have major side effects. "With interferon, you feel lousy the entire time; you're weak and you have no appetite," Weinman explains. "It can cause personality changes and depression, or make pre-existing depression worse." Both interferon and ribavirin also lower a patient's blood counts, increasing the risk of other infections and causing anemia.

Two new drugs, telaprevir and boceprevir, were approved by the FDA last May. But they're only effective alongside interferon and ribavirin. Their own side effects — including a nasty rash and severe bone marrow suppression — compound the misery of the original therapy. They also need to be taken three times daily at exact eight-hour intervals and, in telaprevir's case, with a high-fat diet so it's properly absorbed.

"The ordeal's now even worse, but the new drugs do bring a cure rate that had been below 50 percent closer to 70 percent, and that's huge," Weinman says.

Hepatitis C is all the more difficult to treat because the blood-borne virus spreads most commonly through intravenous drug use, so many patients already have a history of psychiatric problems that are aggravated by the grim course of treatment. "We occasionally get patients who aren't greatly affected by therapy," Weinman says. "But many with hepatitis C are already struggling to cope with their disease before treatment, and the side effects of interferon alone could send them over the edge. That's why we need better treatments."

Targeting the virus

Different proteins — 10 of them, in the case of hepatitis C — make up a virus's structure. By working on HIV, scientists have learned that combinations of drugs, each aimed at a particular protein, are necessary to cut off a virus's survival strategies.

"It's a general principle of treating viruses — if you attack them at multiple sites, they can't mutate away from therapy," Weinman says. "We need potent combinations of new drugs that patients can tolerate long enough to rid themselves completely of hepatitis C."

Boceprevir and telaprevir target a class of viral proteins called proteases. Pharmaceutical companies are also busy developing and testing 20 to 30 different drugs — mostly against other parts of the virus, including its polymerase proteins.

There are additional hepatitis C viral proteins for which drugs could be developed. Weinman is studying one of these lesser-known possibilities, a protein called p7.

"It has similar properties to a protein in the influenza virus, for which the drug amantadine has worked pretty well," he says. "That's what got me interested."

Without p7, the hepatitis C virus is crippled: It can still replicate, but it can't create the packaging material needed to assemble brand-new viruses.

"For a long time, though, nobody knew p7's exact role, only that the virus could not do without it," Weinman says. He and his graduate student, Ann Wozniak, were the first to figure out what p7 actually does: it makes the interior of hepatitis C-infected cells less acid, which is necessary for the virus to function. They published their findings in the journal PLoS Pathogens in September 2010.

Weinman and Wozniak worked with researchers at the University of Leeds in the United Kingdom to deduce p7's function, and are continuing to collaborate to figure out how it could be stifled. In another paper in the journal Hepatology last summer, they described two classes of p7 inhibitors — adamantanes and alkylated imino-sugars — that attack p7 in different ways.

"Most of the current drugs target hepatitis C's early stages of replication," Weinman says. "We're trying instead to prevent replicated viral parts from being assembled." While p7 inhibitors have yet to advance to clinical trials, he reckons it's just a matter of time.

Alcohol's clout

Hepatitis C is most often caught early in people who undergo a health screening as part of a rehabilitation program — or if an observant person notes nondescript symptoms such as fatigue and mild liver tenderness. Most infected people, though, take decades to realize that they have the disease. This is because cirrhosis, or scarring, of the liver, is a stealthy process.

With cirrhosis comes the risk of cancer. Hepatitis C is, in fact, the main cause of liver cancer in Americans.

Besides working on new ways to target the virus with drugs, Weinman wants to better understand hepatitis C's long-term effects on the liver — particularly how alcohol consumption makes hepatitis C run a more aggressive course.

"In the U.S., alcoholism is actually a minor component of liver scarring — 85 percent of people who drink heavily and regularly never get cirrhosis," Weinman says. "That's a pretty surprising statistic, and it indicates that there are natural protective mechanisms against alcohol injury."

Weinman is investigating the potential role of a protein called FOXO3 in shielding the liver from alcohol. "It's a protective factor that gets activated when we either infect laboratory-cultured liver cells with hepatitis C or treat those cells with alcohol," he says. However, feeding alcohol to mice with hepatitis C results in exacerbated liver injury, and under these conditions, FOXO3's activity is significantly diminished.

Like most proteins, FOXO3's surface gets different "tags" added or removed, depending on its cellular environment. These tags alter the protein's function. Weinman and his postdoctoral fellow Irina Tikhanovich have found that in the presence of hepatitis C, FOXO3 is tagged in particular ways that engage its ability to prevent liver inflammation. Alcohol, however, interferes with this process and subverts FOXO's protective function.

Weinman was recently awarded a grant from the National Institutes of Health to continue dissecting the negative impact of alcohol on hepatitis C's progression. He's using some of this funding to explore another conundrum: while FOXO3 protects the liver against hepatitis C or alcohol, it also behaves abnormally in liver cancer.

"FOXO3 normally has another role as a tumor suppressor, but it goes haywire and loses this function in the majority of liver cancer cases," he explains. "It may be that hepatitis C eventually interferes with FOXO3's ability to suppress tumor growth, but we don't know for sure."

Weinman would like to figure out how to manipulate FOXO3 so it both protects the liver from cirrhosis and functions fully as a tumor suppressor. Current chemotherapy drugs produce a slew of harsh side effects and are only marginally effective against liver cancer.

"Chemoprevention is not as sexy; you can't point to Mrs. Jones over there and say you got rid of her liver cancer and saved her life," he says. "But I'm more interested in preventing cancer from ever occurring in patients with cirrhosis than treating cancer that's already developed. I think we'll save more lives this way."

A different approach, and hope for a cure

Through its active liver transplant practice, the KU Medical Center has acquired more than 2,000 tissue samples from the liver biopsies of more than 1,000 patients. These samples allow KU researchers to rapidly test ideas in ways that wouldn't be possible without the multi-year specimen repository, Weinman says.

Several other Liver Center researchers are also using these samples, along with patient histories, to investigate alcohol's influence on hepatitis C. In December 2011, they published a paper in Hepatology showing that alcohol may mask the effects or impair the expression of several nuclear receptor genes which, among other things, regulate the formation of scar tissue that eventually leads to liver cirrhosis, which happens much faster in alcoholics with hepatitis C.

"We haven't determined if there's a direct association between alcohol's effect on nuclear receptors and the progression of hepatitis C," says Richard Gilroy, M.D., a liver transplant specialist at KU Medical Center and one of the paper's authors. "However, it's a likely reason why this disease is more aggressive in alcoholics."

Weinman, who did not contribute to this paper, considers it a good example of how hepatitis C and alcohol might individually alter gene expression in the liver, with each influencing the other's effects.

"I think it's a nice proof-of-principle that the interaction of alcohol and hepatitis C is not the sum of two parts — instead, alcohol is modifying what hepatitis C does," he says.

Ultimately, Weinman and his colleagues are looking forward to greatly improved drugs for hepatitis C, especially the dawning era of interferon-free therapy.

"It's as certain as anything can be in medicine that we're on the cusp of curing this disease in 90 to 95 percent of patients," he says.

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Campaign to Engage 100,000 Healthcare Personnel Behind Needlestick Injury Prevention

4 hours ago

Posted in News, Sharps Safety, PPE & Standard Precautions, Bloodborne Pathogens

Every day, 5.6 million healthcare personnel in the U.S. are put at risk of occupational exposure to HIV, hepatitis C and other life-threatening blood-borne diseases via transmission modes such as needlestick injuries.

Safe in Common, a non-profit organization of healthcare safety advocates is launching a nationwide campaign to unite 100,000 U.S. healthcare personnel who believe current Federal standards for needlestick prevention to be largely inadequate, and that safer devices and other measures are needed to maximize protection to those at risk of harm.

Dr. Mary Foley, Chairperson of Safe in Common, notes, “As president of the American Nursing Association during the adoption of the federal Needlestick Prevention Act in 2000, I was honored to have helped our industry take a vital first step towards protecting healthcare personnel at risk of injury. But we must now come together again to help finish the job. I firmly believe that every needlestick injury is preventable with the right equipment, the right procedures and the right culture. I encourage all U.S. healthcare personnel to join me in the signing of the Safe in Common Pledge.”

Each year, nurses, physicians and other healthcare workers suffer an estimated 800,000 accidental needlestick injuries in U. S. hospitals. More than 1,000 of them become infected with HIV/AIDS or hepatitis B and C and other deadly blood-borne diseases

Safe in Common is a non-profit organization established to enhance and save the lives of U.S. healthcare personnel at risk of harm from needlestick injuries. It is led by Chairperson Mary Foley, PhD, RN, former president of the American Nursing Association and a U.S. leader for needlestick prevention, Healthcare Safety Advocate Nancy Purcell-Holmes, RN, and other industry leaders.

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